Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2
Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2
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DOI：
10.1074/jbc.m308658200
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发表时间：
2003-12-12
影响因子：
4.8
通讯作者：
Hazra, TK
中科院分区：
文献类型：
--
作者：
Dou, H;Mitra, S;Hazra, TK
通过碱基切除修复途径修复基因组中氧化损伤的碱基是由具有广泛底物范围的DNA糖基酶切除这些损伤开始的。新发现的人类DNA糖基酶NEIL1和NEIL2在结构特征和反应机制上与之前表征的NTH1和OGG1不同，但作用于许多相同的底物。然而，NEIL2表现出独特的偏好，从DNA泡中切除病变，而NTH1和OGG1仅对双链DNA有活性。NEIL1也能有效地从气泡和单链DNA中去除胞嘧啶的氧化产物5-羟基尿嘧啶，但对气泡中的8-氧鸟嘌呤没有很强的活性。NEILs与NTH1/OGG1对气泡和双工DNA底物活性的二分法与NEILs对受损和未受损DNA的气泡结构的亲和力相对于双工结构更高一致。这些观察结果表明，NEILs在功能上不同于OGG1/NTH1。转录序列中氧化碱基的OGG1/ nth1独立修复支持了NEILs优先参与转录和/或复制过程中产生的DNA泡损伤修复的可能性。
Repair of oxidatively damaged bases in the genome via the base excision repair pathway is initiated with excision of these lesions by DNA glycosylases with broad substrate range. The newly discovered human DNA glycosylases, NEIL1 and NEIL2, are distinct in structural features and reaction mechanism from the previously characterized NTH1 and OGG1 but act on many of the same substrates. However, NEIL2 shows a unique preference for excising lesions from a DNA bubble, whereas NTH1 and OGG1 are only active with duplex DNA. NEIL1 also excises efficiently 5-hydroxyuracil, an oxidation product of cytosine, from the bubble and singlestranded DNA but does not have strong activity toward 8-oxoguanine in the bubble. The dichotomy in the activity of NEILs versus NTH1/OGG1 for bubble versus duplex DNA substrates is consistent with higher affinity of the NEILs for the bubble structures of both damaged and undamaged DNA relative to duplex structure. These observations suggest that the NEILs are functionally distinct from OGG1/NTH1 in vivo. OGG1/NTH1-independent repair of oxidized bases in the transcribed sequences supports the possibility that NEILs are preferentially involved in repair of lesions in DNA bubbles generated during transcription and/or replication.